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Thesis (M. Sc.(Biochemistry)) -- University of Limpopo, 2020 / Diabetes mellitus has become a global epidemic, particularly type 2 diabetes. Obesity is one of the causes of type 2 diabetes mellitus due to its link with induced insulin resistance. There is no cure for diabetes mellitus and, as such, it is managed by using standard drugs which have side effects, and can be toxic, expensive and unavailable. People have resorted to the use of medicinal plants to treat diabetes and its complications. The aim of this study was to test the anti-obesity and anti diabetic properties of Bidens pilosa crude extract and its sub-fractions using C2C12 myoblasts and 3T3-L1 adipocytes. The crude extract and the most active sub fractions were selected for further analysis because of their ability to stimulate glucose uptake and induction of adipogenesis. Bidens pilosa leaves were selected for this current study. They were firstly extracted using absolute methanol and further subjected to solvent-solvent fractionation to obtain the n-butanol, ethyl acetate, water, hexane, chloroform and 35% water in methanol sub-fractions. Qualitative phytochemical analysis was performed using thin layer chromatography (TLC) and standard chemical tests. Total phenolic and flavonoid content were determined quantitatively using a calorimetric method with Folin-Ciocalteu’s reagent. For their antidiabetic potential, the extracts were evaluated chromogenically and calorimetrically for antiglycation and α-amylase inhibitory activity. The cytotoxicity of the extracts on 3T3-L1 preadipocytes and C2C12 myotubes were determined using the MTT assay. The adipogenesis inducing effect of the extract was tested using the adipogenesis kit. More compounds were found on chromatograms eluted in EMW mobile phase (Ethyl acetate: methanol: water). The extracts were shown to contain a variety of secondary metabolites, and high phenolic and flavonoids contents. Crude, chloroform, n butanol and water sub-fractions had high antioxidant activity. Alpha amylase activity was highly inhibited in the crude extract and all sub-fractions, with the highest inhibitory activity observed in the crude extract and the chloroform, n-butanol and water Sub-fractions (IC50 1.25 ± 2.5 mg/ml). The cytotoxic profiles indicated that all extracts are non-cytotoxic at concentrations of 15.63 µg/ml. Extracts at a concentration of 31.25 µg/ml were shown to stimulate the accumulation of triglycerides using 3T3-L1 adipocytes. The extracts also exhibited significant (P < 0.05) glucose uptake activity. In conclusion, Bidens pilosa contains constituents that inhibit α-amylase, antiglycation formation and modulates uptake of glucose in 3T3-L1 adipocytes. The use of B. pilosa in combination with insulin revealed the synergistic effects in facilitating glucose uptake in both C2C12 myotubes and 3T3- L1 adipocytes. This suggests that there might be some binding compounds found in the plant extracts that are responsible for the stimulation of expression of several genes that encode for proteins involved in the metabolism of glucose. However, the use of B. pilosa, in combination with metformin, results in a decreased glucose uptake. Bidens pilosa have the fast-acting insulin mimetic properties. Furthermore, the plant was shown to stimulate the accumulation of triglycerides in 3T3-L1 adipocytes, signifying the plant can induce adipogenesis at 30µg/ml / South African Medical Research Council (SAMRC)

The present study investigates the self-care and health maintenance strategies undertaken by individuals from Halton Region, Ontario living with type 2 diabetes and receiving assistance from food acquisition services such as community food re-distribution centres and food banks. This qualitative research project pulls narrative and thematic interview data from 18 semi-structured one-on-one interviews analyzed with syndemic theory and social determinants of health frameworks to demonstrate how clustering non-communicable diseases and social conditions disproportionately affect those in the lowest income category, and interact with each other to exacerbate the negative health effects of each condition alone. The contributions of this study are theoretical and applied. Theoretical contributions augment existing evidence for the study of non-communicable diseases using a syndemic model. The study participants demonstrated syndemic clustering of five conditions: type 2 diabetes, food insecurity, low income, poor mental health, and activity limitation. Further, this study suggests an applied element to the syndemic model through an approach to health and diabetes care that incorporates the whole person as opposed to a single disease as a unit of care. As suggested through the findings of research participant testimony, a diabetes health care centre, in addition to traditional diabetes care, would ideally screen and offer care for the other common clustered conditions listed in the syndemic elements above. Thus, the centre would provide nutrition, physical activity, mental health, and social supports to patients. As well, it is recommended that future research contributes to prevention and treatment of non-communicable diseases through social, political, and economic in form of increasing government and healthcare supports for people living with low-income and food insecurity. / Thesis / Master of Arts (MA) / This study looks at how individuals from Halton Region, Ontario maintain their health while living with type 2 diabetes and reduced access to healthy, fresh food. The project uses interview data from 18 one-on-one interviews to demonstrate how people with low income suffer from poorer overall health. Specifically, five conditions affected the study participants’ health: type 2 diabetes, reduced access to healthy food, low income, poor mental health, and reduced financial or physical access to exercise or activities of daily living (activity limitation). To combat these conditions, this study suggests an approach to health and diabetes care that looks at the whole person. Evidence and participant suggestions indicate a diabetes health care centre that screens and offers care for other common conditions that occur such as the elements listed above, and also provides nutrition care, physical activity, and social support to patients.

Major depressive disorder (MDD) is one of the most common psychiatric illnesses worldwide, with pharmacotherapy as a first-line option for the management of this illness. The National Center for Health Statistics found that the use of antidepressants has increased by more than 4 fold in the last 20 years. While SSRI’s act centrally to treat MDD, their peripheral effects are often overlooked. Interestingly, components of the serotonergic system including the serotonin transporter (SERT), serotonin receptors, and enzymes important for serotonin synthesis (tryptophan hydroxylase 1 and 2; Tph1 and Tph2) are affected by SSRI treatment both centrally and peripherally. This disruption of serotonin signaling in the pancreas is of particular interest as there is a considerable link between the serotonin and hedgehog signaling pathways, both of which are important for pancreatic beta cell function. I hypothesize that pancreatic beta cell exposure to the SSRI fluoxetine in vitro will lead to altered hedgehog signaling ultimately resulting in a disruption in insulin secretion. / Thesis / Master of Science in Medical Sciences (MSMS)

Background: South Asians are at an increased risk of developing dysglycemia during and after pregnancy. In pregnant women, dysglycemia often develops in the form of gestational diabetes mellitus (GDM), which may predispose their newborns to adverse health outcomes through abnormal cord blood insulin levels. However, reasons for the elevated risk of dysglycemia in South Asians have not been extensively studied. Genetic factors may contribute to the heritability of GDM and abnormal cord blood insulin levels in South Asians. Objectives: The objectives of this thesis were to test the association of: 1) A type 2 diabetes polygenic risk score with GDM in South Asian pregnant women from the South Asian Birth Cohort (START); 2) maternal and newborn insulin-based polygenic risk scores with cord blood insulin and glucose/insulin ratio in South Asian newborns from START Methods: Three polygenic risk scores were created to test their association with participant data (N=1012) from START. GDM was defined using cut-offs established by the Born in Bradford cohort of South Asian women. The type 2 diabetes polygenic risk score was created in 832 START mothers and included 35,274 independent variants. The maternal and newborn insulin-based polygenic risk scores were created in 604 START newborns and included 1128017 independent variants. Univariate and multiple logistic and linear regression models were used to test the associations between the polygenic risk scores and dysglycemia outcomes. Results: The type 2 diabetes polygenic risk score was associated with GDM in both univariate (OR: 2.00, 95% CI: 1.46-2.75, P<0.001), and multivariable models (OR: 1.81, 95% CI: 1.30-2.53, P<0.001). The maternal insulin-based polygenic risk score was not associated with cord blood insulin or cord glucose/insulin ratio. However, the newborn insulin-based polygenic risk score was associated with cord blood insulin in a multivariable model adjusted for maternal insulin-based polygenic risk score (β = 0.036, 95% CI: 0.002 – 0.069; P=0.038 among other factors. Conclusion: A type 2 diabetes polygenic risk score and a newborn insulin-based polygenic risk score may be associated with maternal and newborn dysglycemia. / Thesis / Master of Science (MSc) / Background: South Asians are approximately two times more at risk for developing gestational diabetes mellitus (GDM) compared to white Caucasians. Genetic factors may contribute to this elevated risk. Polygenic risk scores (PRSs), which combine the effects of multiple disease loci and variants associated with the disease into one variable could be useful in further understanding how GDM develops in South Asians. Methods: Data from the South Asian Birth Cohort (START) was used to test the association of three PRSs with the outcomes of interest. Results: The type 2 diabetes PRS was independently associated with GDM. The insulin-based maternal PRS was not associated with cord blood insulin but the insulin-based newborn PRS was independently associated with cord blood insulin. However, neither the insulin-based maternal nor newborn PRS was associated with cord blood glucose/insulin ratio. Conclusion: The PRSs suggests a possible genetic component, which contributes to abnormal glycemic status development in South Asian mothers and their newborns.

PhD Dissertation / Obesity is a major risk factor for type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), and is attributed to excess energy intake in comparison to energy expenditure. Therapeutics that reduce energy intake in obesity have limited efficacy, with weight loss typically reaching less than 10% of initial body mass, leading to efforts to uncover new therapies that may increase energy expenditure. Unlike lipid-storing white adipose tissue, brown and beige adipose tissues undergo futile cycling, oxidizing lipids and carbohydrates thereby increasing energy expenditure. With obesity, the metabolic activity of brown and beige adipose tissue is reduced, suggesting that restoring adipose tissue thermogenesis may represent a new means to enhance energy expenditure. Previous studies in mice have shown that peripheral serotonin synthesis by the enzyme tryptophan hydroxylase 1 (Tph1) inhibits adipose tissue thermogenesis and contributes to the development of obesity, insulin resistance and NAFLD. However, the primary Tph1 expressing tissue(s) inhibiting adipose tissue futile cycling is not known. In this thesis, we genetically removed Tph1 in mast cells of mice and discovered that this elevated beige adipose tissue activity protecting mice from developing high-fat diet induced obesity, insulin resistance and NAFLD. In contrast to these findings, genetic deletion of Tph1 in adipocytes did not result in protection from obesity, suggesting that mast cells are the primary source of serotonin that inhibits white adipose tissue thermogenesis. Lastly, to determine the importance of adipose tissue thermogenesis in mediating the beneficial metabolic effects of reduced Tph1, mice were housed at thermoneutrality, blocking the requirement for adipose tissue thermogenesis. Under these conditions, mice lacking Tph1 had comparable brown and beige adipose tissue metabolic activity, energy expenditure and adiposity, however, surprisingly, were still protected from insulin resistance and NAFLD. The studies in this dissertation have discovered that mast cell Tph1 is critical for inhibiting adipose tissue thermogenesis and that serotonin plays an important role in promoting NAFLD, independently of its inhibitory effects on adipose tissue thermogenesis. Collectively, these findings further define the roles of serotonin in regulating whole-body energy metabolism, providing critical clues and mechanistic insights for potential therapies to mitigate metabolic diseases. / Dissertation / Doctor of Philosophy (Medical Science) / Obesity, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) can develop when caloric intake exceeds expenditure. In contrast to lipid-storing white fat, brown and beige fat burn calories. Serotonin is a hormone that reduces the burning of calories in fat, therefore finding ways to inhibit its effects on fat tissue without altering serotonin in the brain may lead to new therapies for obesity and other related diseases. In this thesis, we examined potential sources of serotonin that might inhibit the burning of calories in adipose tissue of mice. By reducing the synthesis of serotonin in a white blood cell called mast cells, but not fat cells, mice were protected from obesity, pre-diabetes and NAFLD due to increased activity of beige fat. Moreover, when we kept mice in a warm environment, thus reducing the need for mice to burn calories in brown and beige fat, this eliminated the effects of serotonin to promote obesity, but not pre-diabetes and NAFLD. These studies have identified how serotonin generated from mast cells inhibits the burning of calories in adipose tissue, a finding that may lead to new therapies for obesity, T2D and NAFLD.